Document Type
Article
Publication Date
1-25-2022
Abstract
Immune cells infiltrate the peripheral nervous system (PNS) after injury and with autoimmunity, but their net effect is divergent. After injury, immune cells are reparative, while in inflammatory neuropathies (e.g., Guillain Barré Syndrome and chronic inflammatory demyelinating polyneuropathy), immune cells are proinflammatory and promote autoimmune demyelination. An understanding of immune cell phenotypes that distinguish these conditions may, therefore, reveal new therapeutic targets for switching immune cells from an inflammatory role to a reparative state. In an autoimmune regulator (Aire)-deficient mouse model of inflammatory neuropathy, we used single-cell RNA sequencing of sciatic nerves to discover a transcriptionally heterogeneous cellular landscape, including multiple myeloid, innate lymphoid, and lymphoid cell types. Analysis of cell-cell ligand-receptor interactions uncovered a macrophage-mediated tumor necrosis factor-α (TNF-α) signaling axis that is induced by interferon-γ and required for initiation of autoimmune demyelination. Developmental trajectory visualization suggested that TNF-α signaling is associated with metabolic reprogramming of macrophages and polarization of macrophages from a reparative state in injury to a pathogenic, inflammatory state in autoimmunity. Autocrine TNF-α signaling induced macrophage expression of multiple genes (Clec4e, Marcksl1, Cxcl1, and Cxcl10) important in immune cell activation and recruitment. Genetic and antibody-based blockade of TNF-α/TNF-α signaling ameliorated clinical neuropathy, peripheral nerve infiltration, and demyelination, which provides preclinical evidence that the TNF-α axis may be effectively targeted to resolve inflammatory neuropathies.
Recommended Citation
Wang, Yan; Guo, Lily; Yin, Xihui; McCarthy, Ethan C; Cheng, Mandy I; Hoang, Aline T; Chen, Ho-Chung; Patel, Anushi Y; Allard Trout, Denise; Xu, Erin; Yakobian, Natalie; Hugo, Willy; Howard, James F; Sheu, Katherine M; Hoffmann, Alexander; Lechner, Melissa G; and Su, Maureen A, "Pathogenic TNF-α drives peripheral nerve inflammation in an Aire-deficient model of autoimmunity" (2022). Department of Neurology Faculty Papers. Paper 273.
https://jdc.jefferson.edu/neurologyfp/273
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
35058362
Language
English
Comments
This article is the author’s final published version in Proceedings of the National Academy of Sciences of the United States of America, Volume 119, Issue 425, January 2022, Article number e2114406119.
The published version is available at https://doi.org/10.1073/pnas.2114406119. Copyright © National Academy of Sciences.